A wide variety of viruses are known to cause infection and other forms of disease in man and other animals.
One group of such viruses is the flaviviruses. The genus Flavivirus within the family Flaviviridae consists of approximately 70 viruses. Most of these viruses are transmitted by either mosquito or tick vectors. Several flaviviruses are significant human pathogens, including the four dengue viruses (DEN 1, DEN 2, DEN 3, and DEN 4), yellow fever (“YF”), Japanese encephalitis (“JE”), West Nile (“WN”), and members of the tick-borne encephalitis (“TBE”) serocomplex. Mosquitoes transmit dengue fever throughout tropical and subtropical environments worldwide. Mosquito-borne YF virus is found primarily in tropical and subtropical Africa and South America, whereas JE virus is found in Asia and Indonesia. In addition, to the encephalitic members of the TBE serocomplex, three hemorrhagic viruses have been described: Kyasanur Forest disease (“KFD”), Omsk hemorrhagic fever (“OHF”), and Alkhurma viruses that are found in India, Siberia, and Saudi Arabia, respectively. Currently, the National Institute of Allergy and Infectious Diseases of the U.S. National Institutes of Health includes the following flaviviruses in the category A, B, and C lists: dengue, WN, JE, YF, KFD, and members of the tick-borne encephalitis complex, such as Russian spring summer encephalitis (“RSSE”), central European TBE, and OHF.
In the case of dengue, the viruses are transmitted to man by mosquitoes of the genus Aedes, primarily A. aegypti and A. albopictus. The viruses cause an illness manifested by high fever, headache, aching muscles and joints, and rash. Some cases, typically in children, result in a more severe forms of infection, dengue hemorrhagic fever and dengue shock syndrome, marked by severe hemorrhage, vascular permeability, or both, leading to shock. Without diagnosis and prompt medical intervention, the sudden onset and rapid progression of dengue hemorrhagic fever and dengue shock syndrome can be fatal.
Flaviviruses are the most significant group of arthropod-transmitted viruses in terms of global morbidity and mortality with an estimated one hundred million cases of dengue fever occurring annually. With the global increase in population and urbanization, especially throughout the tropics, and the lack of sustained mosquito control measures, the mosquito vectors of flavivirus have distributed throughout the tropics, subtropics, and some temperate areas, bringing the risk of flaviviral infection to over half the world's population. Modern jet travel and human emigration have facilitated global distribution of dengue serotypes, such that now multiple serotypes of dengue are endemic in many regions. Accompanying this, in the last 15 years has been an increase in the frequency of dengue epidemics and the incidence of dengue hemorrhagic fever and dengue shock syndrome. For example, in Southeast Asia, dengue hemorrhagic fever and dengue shock syndrome is a leading cause of hospitalization and death among children.
Effective vaccines exist for only a few members of the genus Flavivirus, including YF and JE, but there are no effective treatments for the diseases caused by any of the flaviviruses, including dengue, TBE and WN. Many of the viruses in this genus are particularly hazardous and present a serious health risk if released in the United States either by natural routes of infection or by a premeditated attack on the American populace.
In view of the above, a need remains for methods which inhibit the activity of flaviviruses and other viruses, either by inhibiting their propagation or otherwise. The present invention is directed, in part, to addressing this need.